This Mentored Research Scientist Development Award will allow Dr. Coker to extend his work in glucose metabolism performed in animal models into the pathogenesis of insulin resistance in humans. Dr. William J. Evans and Dr. Philip A. Kern will serve as the Co-Mentors for this project. Excessive caloric intake or the lack of physical activity contributes to a positive caloric balance, leading to excess visceral adipose tissue deposition. The pathogenic consequences of visceral obesity usually includes hepatic and skeletal muscle insulin resistance, hyperglycemia, and hyperinsulinemia, and abnormal lipid metabolism eventually leading to type 2 diabetes (T2D). Although caloric restriction and/or exercise training are known to decrease risks associated with T2D, it has been difficult to separate the independent influence of weight loss from exercise training on insulin resistance. We propose to examine the effects of a caloric restriction and/or aerobic exercise training on hepatic and peripheral insulin action using a somatostatin, multi-stage, euglycemic clamp technique in overweight, glucose intolerant men and women. We will recruit 60, 50-80 y old women and men, who will be randomized into one of the following four groups: 1) caloric restriction with weight loss, 2) exercise training without weight loss, 3) exercise training with weight loss, and 4) controls (no dietary or exercise intervention). Dr. Evans has extensive experience in the management of dietary control and exercise training studies. In addition, Dr. Kern will provide specific training in cellular/molecular biology. We will test the hypotheses that 1) caloric restriction will improve hepatic and peripheral insulin action, 2) exercise training without weight loss will only improve peripheral insulin action, 3) exercise training with weight loss will improve hepatic and peripheral insulin action, 4) hepatic insulin action will improve in proportion to the decrease in visceral fat, and that 5) weight loss and exercise training will induce changes in skeletal muscle lipid metabolism through different mechanisms. Since people with impaired glucose tolerance are much more susceptible to the development of T2D, understanding the specific influence of the above mentioned therapeutic regimens on the pathogenesis of insulin resistance has extremely important public health implications. Furthermore, the proposed studies, mentors, co-investigators, and institutional commitment at the University of Arkansas for Medical Sciences provide an outstanding environment for Dr. Coker to develop into an independent basic scientist in diabetes research.